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Superantigens
Written by Tim Sheppard MBBS BSc. Created 8/2/10; last updated 9/2/10

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What is a superantigen?

An important molecule that has a big impact on the immune system is the super-antigen. Unsurprisingly, it is an antigen, and equally unsurprisingly, it is a bit more exciting than a normal antigen. In order to understand it, you need to understand how acquired immunity normally works - because with superantigens, the process of acquired immunity goes a little bit wrong.

In the normal process of acquired immunity, the body reacts to a foreign antigen by presenting it to immune cells such as T-cells. Those specific T-cells which have a T-cell receptor that corresponds to the antigen will then proliferate or copy to produce loads of identical cells that can respond to the threat.

The important thing here is that only those T-cells which respond to that specific antigen will proliferate. The immune system is cleverly set up so that it will only react to the antigens that it is facing. When you're facing an enemy, you only need a weapon that is going to make a difference. If your house filled with ants, weed killer isn't going to help. However, if you house filled with weeds, that weed killer is going to be useful. When faced with a threat, you want something that can deal with that threat. The acquired immune system is set up so that only the T-cells with the relevant receptor will respond.

The problem comes when the body overreacts. This is what happens with superantigens. Instead of just the specific T-cells being activated by the antigen, superantigens activate a much bigger proportion of them. Instead of just having extra T-cells that are specific to the one antigen, you have extra copies of all kinds of T-cells. The body is suddenly flooded with these immune cells - and, more importantly, it is flooded with all of the chemicals that these superantigens produce, such as TNF-alpha. This leads to the problems explained elsewhere.

One way of thinking about superantigens is like a molecule that invaders produce as a defence against our own immune systems. By tricking the immune system into over-reacting, the body fails to produce an effective response to the bug, and in some cases can actually cause serious or life-threatening harm to itself.


How do superantigens work?

Superantigens cause the immune system to overreact by activating loads of T-cells instead of just the ones that are specific for the superantigen. How? This seems impossible, because the T-cell receptors each have a specific shape which is different between different T-cells. A T-cell will only be activated if the T-cell receptor is activated by the specific antigen it is designed to react to. Two T cells should not be activated by the same thing - so how do different T-cells with different T-cell receptors get activated by one superantigen?

This is because the superantigen doesn't bind to the main site of the T-cell receptor. If the main active site of the T-cell receptor is the bit which is different between each receptor, a normal antigen will only be able to activate one T-cell because only one receptor will be activated by the antigen. However, if an antigen manages to activate a T-cell without binding to that specific site, it might be able to activate lots of T-cells. This is what happens with superantigens.

So, an MHC Class II molecule on the surface of an antigen presenting cell will present any old antigen. If a T-cell comes along which is not normally activated by that antigen, it won't be activated. However, if a superantigen binds to the side of the MHC Class II molecule first, and then a T-cell turns up, it can bind to the T-cell receptor as well in such a way that the T-cell becomes activated despite the antigen being the wrong kind for that T-cell.

The superantigen usually binds to a part of the T-cell receptor called the V-beta element. The T-cell makes its receptor by selecting from a library of elements, and when it is choosing the V-beta part, it only has about 50 options to choose from. Therefore, the V-beta bit won't change much between T-cells - so a superantigen only needs to be able to bind one V-beta element in order to activate loads of T-cells.

In fact, some superantigens are able to bind to several different V-beta elements. Even if two T-cells are completely different, if a superantigen is able to bind the V-beta elements on both, if will be able to activate both.

Instead of activating 1 in 10,000 specific T-cells, superantigens can activate as many as 1 in 5 of the whole T-cell population.


What do superantigens do?

The effect of the body's over-reaction to superantigens is somewhat catastrophic. For a start, the excess activation of T-cells leads to considerable production of a range of different cytokines, particularly tumour necrosis factor alpha (TNF-alpha). This is involved in normal immune processes, but is particularly responsible for causing short-term inflammation and in the case of superantigens, is produced in amounts that are far too high.

By reacting in this way, the body produces a massive inflammatory response which, at its worst, is known as toxic shock syndrome. This involves widespread capillary leak, leading to shock and leakage of fluid into peripheral tissues and the lungs. This can further result in respiratory distress syndrome, widespread organ failure, coma and even death.

Even if the body survives this, the huge growth in number of T-cells is not manageable, and release of certain other chemicals leads to T-cells being inactivated or killed off. Instead of a more active immune system, the body ends up with fewer working T-cells to combat infection and as a result is more prone to damage from the original infection.

Unfortunately it doesn't end here. On top of all that, superantigens have effects that have nothing to do with T-cells. They are the cause of certain types of food poisoning, causing you to feel sick. They can also cause monocytes to release chemicals that will attract neutrophils, which further worsens the inflammation in a particular area.

Perhaps worst of all is the way in which superantigens can interact with other bacterial proteins. If superantigens and endotoxins are released at the same time, the effect is even bigger than the effect of each of them added together; it's as though they help each other to have an even worse affect than they could have managed if they weren't helping each other. This is called a synergistic effect, and in the case of superantigens with endotoxins, it makes them as much as 50,000 times as powerful. Scary, hey?

The best way to try and deal with these proteins is to fight them in three different areas. First, look after the patient as a whole by dealing with their shock (e.g. giving fluids, or medications that can help to bring the blood pressure back up). Second, get rid of whatever's producing the superantigen - usually this means giving an appropriate cocktail of antibotics. Third, dampen down the over-active immune response with steroids or, in certain circumstances, intravenous immunoglobulin.


Further Reading